Atrial fibrillation is a form of heart disease that afflicts millions of people. It is a condition in which the normal contraction of the heart is interrupted, primarily by abnormal and uncontrolled action of the atria of the heart. The heart has four chambers: the right atrium, right ventricle, the left ventricle, and the left atrium. The right atrium pumps de-oxygenated blood from the vena cava to the right ventricle, which pumps the blood to the lungs, necessary for return flow of de-oxygenated blood from the body. The right atrium contracts to squeeze blood into the right ventricle, and expands to suck blood from the vena cava. The contractions normally occur in a controlled sequence with the contractions of the other chambers of the heart. When the right atrium fails to contract, contracts out of sequence, or contracts ineffectively, blood flow within the heart is disrupted. The disruption of the normal rhythm of contraction is referred to as an arrhythmia. The arrhythmia known as atrial fibrillation can cause weakness due to reduced ventricular filling and reduced cardiac output, stroke due to clot formation in a poorly contracting atria (which may lead to brain damage and death), and even other life threatening ventricular arrhythmias.
Atrial defibrillator is a therapy being developed for atrial fibrillation. Atrial defibrillators are typically implantable electrical therapy devices which deliver defibrillating energy to the atrium to terminate arrhythmias. They sense the electrical activity of the atrium and deliver an electrical shock to the atrium when the electrical activity indicates that the atrium is in fibrillation. Electrical defibrillation has two major problems: the therapy causes substantial pain and has the potential to initiate a life threatening ventricular arrhythmia. The pain associated with the electrical shock is severe and unacceptable for many patients. Unlike electrical ventricular defibrillators where the patient loses consciousness prior to receiving therapy, the patient who suffers an atrial arrhythmia is conscious and alert when the device delivers electrical therapy.
The potential exists for inappropriate induction of ventricular fibrillation by the shock intended to defibrillate the atrium. The induction of ventricular fibrillation has great potential to result in death in just a few minutes if no intervening therapy is provided. Careful algorithms to deliver shocks to the periods in the ventricular contraction cycle when the heart is not susceptible to shock induced ventricular fibrillation have been developed to reduce the potential of this risk. If the problem of patient pain can be overcome, atrial defibrillators could be used in a large portion of the patient population that suffer from atrial fibrillation.
Pharmacological Atrial Defibrillators
For some time, doctors have treated atrial fibrillation with drugs injected intravenously or administered orally. Recent literature describes the potential for the delivery of drugs to the heart on demand to terminate arrhythmias. The concept has been suggested for use in the atrium to treat atrial fibrillation. Arzbaecher, Pharmacologic Atrial Defibrillator and Method, U.S. Pat. No. 5,527,344 (Jun. 18, 1996) describes a pharmacological atrial defibrillator and method for automatically delivering a defibrillating drug into the bloodstream of a patient upon detection of atrial arrhythmias in order to terminate the atrial arrhythmias. Arzbaecher teaches that unspecified defibrillating drugs should be injected into the bloodstream with a large initial dose followed by delivery of a continuous smaller dose (this is the "two-compartment pharmacokinetic model" discussed in the Arzbaecher patent). By delivering agents to a blood vessel and maintaining a therapeutic level of drugs in the blood stream, Arzbaecher requires systemic effects to be achieved in order to terminate atrial arrhythmias. In other words, if drugs injected according to Arzbaecher are to have any effective concentrations within the heart, a large amount must be injected in the blood stream to ensure that an adequate dose will be delivered to the affected area of the heart. While the drugs are in the blood stream, they are available throughout the body to cause side effects on all other organs.
There are several disadvantages to the transient introduction of systemic drug levels by an implantable device. Systemic effects resulting from such delivery may result in detrimental effects to ventricular cardiac conduction. These detrimental effects could be life threatening. The large amount of drugs required for systemic delivery of therapeutic doses demands a larger, less comfortable device than smaller dosages would allow. The large quantity of drug in the implantable reservoir of such a system is potentially more dangerous if it develops a leak or is ruptured. Such a large single dosage will require a reservoir that requires frequent follow ups for refilling post therapy by a clinician. Lastly, the large quantities of drug required to obtain therapeutic levels in the entire body may cost substantially more than that required to treat a specific site within the heart. The system described by Arzbaecher has one primary advantage over electrical atrial defibrillation: the delivery of therapy to terminate an arrhythmia does not cause patient pain, and some recent abstracts have appeared in the literature which suggest that this technique is viable. See Arzbaecher, et al., Development Of An Automatic Implanted Drug Infusion System For The Management Of Cardiac Arrhythmias, 76 IEEE Proc. 1204 (1991); Bloem, et al., Use Of Microprocessor Based Pacemaker To Control An Implantable Drug Delivery System, Computers in Cardiology 1 (1993); Bloem, et al., Microprocessor Based Automatic Drug Infusion System For Treatment Of Paroxysmal Atrial Fibrillation, 26S J. Electrocardiogr. 60 (1993); and Wood, et al., Feedback control of antiarrhythmic agents, in Molecular Interventions and Local Drug Delivery, (W B Saunders 1995).
Drug delivery directly into the heart has been proposed for other conditions. In my own prior patent, Altman, Implantable Device for the Effective Elimination of Cardiac Arrythmogenic Sites, U.S. Pat. No. 5,551,427 (Sep. 3, 1996) I describe an implantable substrate for local drug delivery at a depth within the heart. The patent shows an implantable helically coiled injection needle which can be screwed into the heart wall in the ventricles and connected to an implanted drug reservoir outside the heart. This system allows injection of drugs directly into the wall of the heart by merely the injection of drugs through the skin into the reservoir. The patent also shows a helical coil coated with a coating which releases drug into the myocardium. This drug delivery may be performed by a number of techniques, among them infusion through a fluid pathway, and delivery from controlled release matrices at a depth within the heart. Co-pending application Ser. No. 08/881,685 by Altman and Altman, describes some additional techniques for delivering local pharmacological agents to the heart.
Other implanted drug delivery systems have been proposed. Levy, System for Controlled Release of Antiarrhythmic Agents, U.S. Pat. No. 5,387,419 (Feb. 7, 1995), describes the placement of controlled release matrices on the surface of the epicardium (on the outside of the heart) for delivery of antiarrhythmic agents, but all dosage forms described are for steady state drug delivery and do not address the advantages of transient drug delivery from an implantable epicardial structure. In addition, the device described by Levy does not address the critical issue of surgical access to the epicardial surface.
Controlled release matrices are drug polymer composites in which a pharmacological agent is dispersed throughout a pharmacologically inert polymer substrate. Sustained drug release takes place via particle dissolution and slowed diffusion through the pores of the base polymer. Prior work has shown that antiarrhythmic therapy administered by epicardial application of controlled release polymer matrices is effective in treating and preventing ventricular arrhythmias in canine ventricular tachycardia model systems [Siden, et al., Epicardial Controlled Release Verapimil Prevents Ventricular Tachycardia Episodes Induced by Acute Ischemia in a Canine Model, 19 J. Cardiovascular Pharmacology 798 (1992).] This work shows the viability of controlled release therapy delivered locally for the treatment of arrhythmias. This work is identical to that described by Levy above in that drug delivery structures are placed on the outside surface of the heart during open heart surgery. No delivery at a depth within the heart is described, there is no discussion of how one would implant the structure non-invasively, and there is no discussion of how one would deliver drugs upon demand to the heart.
Cardiac Pacing
In the past, devices implanted into the heart have been treated with anti-inflammatory drugs to limit the inflammation of the heart caused by the wound incurred while implanting the device itself. For example, pacing leads have incorporated steroid drug delivery to limit tissue response to the implanted lead, and to maintain the viability of the cells in the region immediately surrounding the implanted device. Berthelson, Medical Electrical Lead Employing Improved Penetrating Electrode, U.S. Pat. No. 5,002,067 (Mar. 26, 1991) describes a helical fixation device for a cardiac pacing lead with a groove to provide a path to introduce anti-inflammatory drug to a depth within the tissue. The groove does not provide a patent fluid pathway to a depth within the heart, no tube end to end is described, and the device is designed for pacing the heart. No descriptions of using antiarrhythmic agents or other approaches are described.
Moaddeb, Myocardial Steroid Releasing Lead, U.S. Pat. No. 5,324,325 (Jan. 24, 1994) describes a myocardial steroid releasing lead whose tip of the rigid helix has an axial bore which is filled with a therapeutic medication such as a steroid or steroid based drug. There is no fluid pathway from the proximal end of the catheter, the drug delivery structure is limited in its size, the device is designed for cardiac pacing. Moaddeb describes a reservoir that is small in that it fills only the core region of the distal portion of a helix historically formed of 0.010 inch diameter to 0.012" diameter wire.
Vachon, Implantable Stimulation Lead Having an Advanceable Therapeutic Drug Delivery System, U.S. Pat. No. 5,447,533 (Sep. 5, 1995) and U.S. Pat. No. 5,531,780 (Jul. 2, 1996) describe pacing leads having a stylet introduced anti-inflammatory drug delivery dart and needle which is advanceable from the distal tip of the electrode. No end to end tube is provided, and no means for transient delivery of agents in an implantable setting is provided.
Cardiac Ablation
The infusion of different fluids to a depth within the myocardium has been described in the patent literature as being useful for ablation. Lesh, Cardiac imaging and ablation catheter, U.S. Pat. No. 5,385,148 (Jan. 31, 1995) describes a cardiac imaging and ablation catheter in which a helical needle may be used to deliver fluid ablative agents, such as ethanol, at a depth within the tissue to achieve ablation. Lesh proposes permanently killing the tissue with a one time application of ethanol such that the heart is permanently damaged, not controlled. In one embodiment he does describe the potential of temporarily deadening the tissue with either lidocaine or iced saline solution, but this is merely in preparation of killing the tissue. The entire patent here teaches away from implantable materials and applications as the fundamental device use is for acute ablation procedures. No means for transient delivery of agents in an implantable setting is provided.
Mulier, Method and Apparatus for Ablation, U.S. Pat. No. 5,405,376 (Apr. 11, 1995), Method and Apparatus for R-F Ablation, U.S. Pat. No. 5,431,649 (Jul. 11, 1995); and Method for R-F Ablation, U.S. Pat. No. 5,609,151 (Mar. 11, 1997) each describe a hollow helical delivery needle to infuse the heart tissue with a conductive fluid prior to ablation to control the lesion size produced. In addition delivery of an agent to affect cardiac conduction to evaluate an ablation site, and delivery of RF energy to the helical needle are disclosed. In all embodiments the device is described as an acute use ablation catheter using different techniques. No means for transient delivery of agents in an implantable setting is provided.
Cardiovascular Restenosis
Igo, Apparatus And Method For Transpericardial Delivery Of Fluid, U.S. Pat. No. 5,634,895 (Jun. 3, 1997) shows a technique for delivering drugs locally to different regions of the surface of the heart and within the pericardial sac via a subxiphoid surgical route, for treating vascular thrombosis and restenosis. The subxiphoid surgical route requires open chest surgery, and penetration of the pericardial sac. Such invasive procedures can be complicated by pericarditis and pericardial tamponade. No techniques for less invasive delivery of bioactive agents to the surface of the heart or into the pericardial space are described. No systems for transient delivery, or transient delivery upon demand are described. No techniques for delivering antiarrhythmic agents or terminating atrial arrhythmias are addressed.
Antiarrhythmic Drugs
There are a number of viable pharmacologic therapies that are also available. Drugs that predominantly affect slow pathway conduction include digitalis, calcium channel blockers, and beta blockers. Drugs that predominantly prolong refractoriness, or time before a heart cell can be activated, produce conduction block in either the fast pathway or in accessory AV connections including the class IA antiarrhythmic agents (quinidine, procainimide, and disopyrimide) or class IC drugs (flecainide and propafenone). The class III antiarrhythmic agents (sotolol or amiodorone) prolong refractoriness and delay or block conduction over fast or slow pathways as well as in accessory AV connections. Temporary blockade of slow pathway conduction usually can be achieved by intravenous administration of adenosine or verapamil. [Scheinman, Supraventricular Tachycardia: Drug Therapy Versus Catheter Ablation, 17 Clinical Cardiology II-11 (1994)]. Other agents such as encainide, diltiazem, and nickel chloride are also available.
Drugs currently used for antiarrhythmia control can actually kill people. The Cardiac Arrhythmia Suppression Trial showed that specific agents delivered systemically resulted in substantially higher mortality rates than those individuals receiving no drugs at all. [The Cardiac Arrhythmia Suppression Trial (CAST) Investigators, The effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction, 321 N. Engl. J. Med. 406 (1989). Echt, et al., Mortality and morbidity in patients receiving encainide, flecainide, or placebo--the Cardiac Arrhythmia Suppression Trial, 324 N. Engl. J. Med. 781 (1991).] This is likely due to the problematic pro-arrhythmia effects of systemic drug delivery. Minimization of dose by local transient drug delivery has potential to eliminate the side effects of these antiarrhythmic agents. There is a need to improve pharmacological therapy for the treatment of arrhythmias by providing for local delivery of these and other agents to regions within the heart tissue.
There are embodiments of this invention which incorporate noninvasive surgical techniques for delivering drugs to the pericardial space and overcoming the difficulties of the invasive sub-xiphoid procedure described by Igo. In order to develop these techniques it is important to touch on the prior art regarding pericardial access and delivery.
Pericardial Access and Delivery
There are a number of approaches for placing devices epicardially. Crosby, Apparatus for cardiac surgery and treatment of cardiovascular disease, U.S. Pat. No. 4,181,123 (Jan. 1, 1980) and Method And Apparatus For Permanent Epicardial Pacing Or Drainage Of Pericardial Fluid And Pericardial Biopsy, U.S. Pat. No. 4,319,562 (Mar. 16, 1982) and Chin, et al., Method And Apparatus For Providing Intrapericardial Access And Inserting Intrapericardial Electrodes, U.S. Pat. No. 5,033,477 (Jul. 23, 1991) to disclose methods for placing electrodes in contact with the heart muscles from within the pericardial space without the need for a thoracotomy. Access to the pericardial space is gained via a sub xiphoid approach. This involves penetrating the chest wall below the xiphoid process.
The sub xiphoid route has several disadvantages. First, because the pericardial sac which surrounds the heart is a tight fitting fibrous membrane, the pericardial space is so small that it is difficult to penetrate the sac without also puncturing, and thereby damaging the heart itself. Second, accessing the heart via a subxiphoid route entails a high risk of infection. These are likely to account for the failure of these methods to be adopted in common clinical practice.
Several patents, including Elliott, et al., Method For Transvenous Implantation Of Objects Into The Pericardial Space Of Patients, U.S. Pat. No. 4,884,567 (Dec. 5, 1989) and Elliott, Defibrillator System With Cardiac Leads And Method For Transvenous Implantation, U.S. Pat. No. 4,946,457 (Aug. 7, 1990) and Cohen, et al., Travenously Placed Defibrillation Leads, U.S. Pat. No. 4,998,975 (Mar. 12, 1991) have proposed methods for transvenous implantation of electrodes into the pericardial space. A catheter is introduced through a vein to the right atrium where the lateral wall is penetrated in order to introduce electrodes into the pericardial space. A major problem encountered by these methods is how to penetrate the lateral atrial wall without puncturing the tight fitting pericardium.
The methods of these patents attempt to solve this problem through several elaborate schemes. One scheme involves using complex catheters to attach to the lateral wall and to pull it back away from the pericardium prior to penetrating the atrial wall in order to avoid puncturing the pericardium. Another approach involves injecting a fluid into the pericardial space to distend the pericardium away from the lateral atrial wall prior to penetrating the wall.
Cohen, Method and System for Implanting Self Anchoring Epicardial Defibrillation Electrodes, U.S. Pat. No. 4,991,578 (Feb. 12, 1991) discloses a method for implanting epicardial defibrillation electrodes into the pericardial space via the subxiphoid route. As discussed above, it is difficult to penetrate the pericardial sac via the sub xiphoid route without also puncturing and thereby damaging the heart itself. Like the method discussed directly above, the '578 patent discloses injecting a fluid into the pericardial space or attaching and pulling on a catheter to distend the pericardial sac away from the heart.
Cohen, Transvenously Placed Defibrillation Leads Via An Inferior Vena Cava Access Site And Method Of Use, U.S. Pat. No. 4,991,603 (Feb. 12, 1991) discloses a method for implanting defibrillation electrodes in contact with epicardial or pericardial tissue from an inferior vena cava access site. A hole is made in the inferior vena cava and a catheter is transvenously inserted into the inferior vena cava and out through a hole into the chest cavity adjacent to the heart. The catheter then pierces the pericardial sac to access the pericardial space. The risk of damaging the heart muscle remains high with this method.
The pericardial sac has been used for containment of pharmacological agents for a number of years in experimental settings, but delivery has required open chest surgery to access the pericardial space. Ellinwood, Apparatus And Method For Implanted Self-Powered Medication Dispensing, U.S. Pat. No. 4,003,379 (Jan. 18, 1977) and Ellinwood, Self-Powered Implanted Programmable Medication System And Method, U.S. Pat. No. 4,146,029 (Mar. 27, 1979) disclose an implantable medication dispensing apparatus which is adapted to dispense drugs to the pericardial sac over a long period of time, for example to prevent arrhythmias. The Ellinwood patents do not teach a method for routing drugs to the pericardial sac. Epicardial delivery of pharmacological agents to the heart is similar to that described in Igo, Apparatus And Method For Transpericardial Delivery Of Fluid, U.S. Pat. No. 5,634,895 (Jun. 3, 1997) which describes a balloon catheter for sub xiphoid access. Levy, System for controlled release of antiarrhythmic agents, U.S. Pat. No. 5,387,419 (Feb. 7, 1995) describes implantable control release matrices. Verrier, Method For Transvenously Accessing The Pericardial Space Via The Right Auricle For Medical Procedures, U.S. Pat. No. 5,269,326 (Dec. 14, 1993) describes a technique for accessing the pericardium through the right atrial appendage and describes the possibility of infusing the pericardium with antiarrhythmic agents.
No systems or techniques for local drug delivery to the epicardial surface of the heart upon demand have been described. In addition, no means of creating a viable atriotomy closure after transatrial implantation of devices has been described. Further, no means has been provided for hybrid local drug delivery therapies involving electrical therapy and ablative therapy for the treatment of arrhythmias.
Cardiac Bypass
There are two general types of cardiac bypass graft procedures: stopped heart procedures and beating heart procedures. Traditional bypass and its minimally invasive counterpart developed by Heartport, Inc. in Redwood City, Calif., USA involve stopping the heart with a cardioplegia solution and performing circulatory support by cardiopulmonary bypass. Although excellent success has been achieved with conventional cardiac bypass grafting employing cardiopulmonary bypass for circulatory support, the major causes of mortality and morbidity are due to the use of cardiopulmonary bypass as well as manipulation of the aorta by either cross clamping or placement of proximal grafts that lead to atherosclerotic cerebral emboli. Cardiopulmonary bypass introduces well known adverse effects such as hemodilution, stroke, renal insufficiency, coagulopathic bleeding and incitement of the systemic inflammatory response. [M. J. Mack, International Journal of Cardiology, 62 Suppl. 1, 1997, S73-S79.] In addition, cardiopulmonary bypass has the disadvantage in that it accounts for a substantial portion of the expensive procedural cost. The technology of cardiopulmonary bypass is described in recent patents devising new methods for managing cardioplegic fluids such as U.S. Pat. Nos.: 5,423,769; 5,423,749; 5,609,571; 5,643,191; 5,702,358; 5,540,841.
Beating heart cardiac bypass surgery, such as the "MIDCAB" procedure developed by CardioThoracic Systems, Portola Valley, Calif. eliminates cardiopulmonary bypass and its inherent disadvantages, but it has its own complications. Beating heart surgery requires the surgeon to perform delicate techniques on a heart that is beating and full of blood, making the procedure much less precise and controllable. Some of these difficulties have led to reservations on the part of some physicians regarding both the "midcab" approach as well as the "port access" approaches for minimally invasive cardiac surgery. [Lawrence I. Bonchek and Daniel J. Ullyot: Minimally Invasive Coronary Bypass A Dissenting Opinion, Circulation, 1998; 98: 495-497.] Advantages of beating heart surgery has led some to attempt the development of complicated surgical compensation techniques to eliminate the perception of heart motion for the surgeon and improve the precision of the procedure. Others have developed methods of physically stabilizing the heart with either devices such as the Medtronic Octopus or less expensive devices formed in the operating suite using wet cotton tape [Vincenzo Lucchetti and Gianni D. Angeini: An Inexpensive Method of Heart Stabilization During Coronary Artery Operations without Cardiopulmonary Bypass, Ann. Thorac. Surg. 1998; 65:1477-8.]. Altman, in pending U.S. application Ser. No. 09/057,060 has described an approach between stopped heart cardiac surgery and beating heart cardiac surgery, which will be developed further here.